Autophagy—A double‐edged sword in oncology

Apel, Anja; Zentgraf, Hanswalter; Büchler, Markus W.; Herr, Ingrid

doi:10.1002/ijc.24500

Cited by 144 publications

(110 citation statements)

References 69 publications

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“…Notably, the pro-survival function of autophagy may help cancer cells to survive in nutrient-limited environments and to resist ionizing radiation and chemotherapies (32). As shown in the present study, an autophagic inhibitor can suppress HCC cell growth during I/H, suggesting that I/H is likely to initiate an autophagic response to promote HCC cell survival, potentially accounting for the increased HCC cell proliferation after TACE.…”

Section: Discussionsupporting

confidence: 60%

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Yang

Chen

et al. 2012

Int J Oncol

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Abstract. Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Autophagy is the intracellular bulk degradation process for long-lived proteins and dysfunctional organelles. In this study, we report that autophagy plays a role in HCC cell proliferation in response to ischemia-hypoxia (I/H) and reperfusion and discuss its potential therapeutic implications. By establishing a simulated model in cultured HepG2 (p53 wild-type) and Hep3B (p53 null) hepatoma cells in vitro, we found that exposure to I/H induced a significant increase in microtubule-associated protein 1 light chain 3 (LC3) lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was stimulated upon acute I/H exposure compared to that of control, inhibition of autophagy by autophagy-related protein 7 interference abolished it. In addition, the steady-state levels of sequestosome 1 (p62) in both HepG2 and Hep3B cells were reduced following I/H exposure, supporting the notion that acute I/H induces autophagy. Intriguingly, the p62 level further decreased during reperfusion following I/H, accompanied by increased LC3 lipidation. The intracellular reactive oxygen species (ROS) accumulated during acute I/H exposure and persisted through reperfusion in both HepG2 and Hep3B cells and the ROS levels increased at a much faster rate during reperfusion than during I/H periods in both cells. Autophagy functions as a promoter for HCC cell survival during acute I/H and reperfusion and this also points to potential therapy for hepatoma by perturbing the acute I/H-reperfusionautophagy axis. IntroductionHepatocellular carcinoma (HCC) causes almost half a million deaths each year, making HCC the third most common cause of cancer-related mortality (1). Despite recent progress in diagnostic and therapeutic management, HCC prognosis remains poor (2). HCC is often diagnosed at an advanced stage when resection, transplantation, percutaneous and transarterial interventions are often of limited efficacy. Although sorafenib has demonstrated promising results in improving the survival and the time to progression in patients with advanced HCC, HCC is frequently resistant to conventional chemotherapy and radiotherapy (3).Ischemia-hypoxia (I/H) and reperfusion constitute key components of many pathological conditions associated with solid tumors. As the liver is a key metabolic organ in humans, the abnormal vasculature network, high interstitial pressure and high proliferation rate of HCC cells result in different types of hypoxia, such as transient hypoxia and chronic hypoxia (4). In response to I/H, the formation of tumor collateral vessels can induce subsequent reperfusion, resulting in oxidative stress (5). Consistent with the described scenario, HCC cells are reportedly more sensitive to I/H and reperfusion injury than normal liver tissue (6).Transcatheter arterial chemoembolization (TACE) has become one of the most widely used treatments for patients with HCC as a palliative measure (7). However, increased microves...

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Section: Discussionsupporting

confidence: 60%

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Yang

Chen

et al. 2012

Int J Oncol

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“…104 However, whether autophagy contributes to TCD after cytotoxic therapy or represents a mechanism of resistance is still a matter of debate. During unfavorable metabolic conditions (for example, cell stress/damage by cytotoxic compounds), apoptosisdefective tumor cells can survive by invoking a protective autophagic process, that is, degradation of proteins and organelles to provide amino acids, fatty acids and nucleotides for reuse.…”

Section: Effects On Tumor Cells and On Tumor Microenvironmentmentioning

confidence: 99%

“…During unfavorable metabolic conditions (for example, cell stress/damage by cytotoxic compounds), apoptosisdefective tumor cells can survive by invoking a protective autophagic process, that is, degradation of proteins and organelles to provide amino acids, fatty acids and nucleotides for reuse. 102,104 Some findings suggest that prolonged stimulation of autophagy may be detrimental to cancer cells and that therapies that inhibit autophagy may lead to enhanced tumor growth. 105 Other studies, however, support the use of autophagy inhibitors as potentiators of anticancer agents.…”

Section: Effects On Tumor Cells and On Tumor Microenvironmentmentioning

confidence: 99%

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

et al. 2013

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Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

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“…As a double-edged sword, autophagy plays a dual role in many diseases [116] . For example, autophagy acts both as a tumor suppressor and a protector of cancer cell survival in tumorigenesis [117] . A growing body of evidence demonstrates that cellular decisions toward autophagy depend on disease type, stage, microenvironment and drug treatment.…”

Section: Therapeutic Implications For Autophagy Regulatorsmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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Autophagy—A double‐edged sword in oncology

Cited by 144 publications

References 69 publications

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

Application and interpretation of current autophagy inhibitors and activators

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